Breast cancer is the most common malignancy in women worldwide and is currently the leading cause of cancer-related mortality. More than 1 million cases are diagnosed every year, which affects 10-12% of the female population and accounts for 500, 000 deaths per year worldwide. While significant advances have been made over the last 30 years, these statistics indicate that novel approaches are essential for early detection and treatment of breast cancer. Preclinical studies and clinical trials have demonstrated that immunotherapy can effectively treat cancer;however, breast cancer immunotherapy needs to also focus on removing negative factors that could inhibit the immune response in order to maximize its therapeutic effects. Natural killer T (NKT) cells are important in regulating immune responses to tumors. Nevertheless, the anti-tumor effects mediated by these cells may be compromised because cancer patients have a reduction in both NKT cell number and function. The mechanisms by which NKT cells are functionally reduced in cancer patients has yet to be identified. It is known that lipids are frequently shed by tumors and can block immune responses. In fact, lipid levels are higher in the mammary tissue and sera of breast cancer patients compared to healthy controls. Thus, we hypothesize that lipid shedding by breast cancers cells is a mechanism used to inhibit NKT cell activation and possibly cause their death. We will test our hypothesis with the following aims: (1) To determine if blocking breast cancer-associated ganglioside biosynthesis can restore NKT cell function;(2) To determine whether the restoration of NKT cell function results in tumor clearance;and (3) To determine whether ganglioside over-expression correlates with a decrease in V124+NKT cells or poor clinical outcome. The information gained from these studies will enhance our knowledge of the role of NKT cells in mediating breast cancer regression. Collectively, this proposal strongly implicates a role for the modulation of NKT cell activity in the development of new therapeutic agents designed to treat breast cancer. PUBLIC HEALTH RELEVANCE: Early-onset breast cancers in women with BRCA1 mutations is more difficult to treat/manage due to its aggressive nature, generally advanced stage at presentation, and because the patients are not candidates for endocrine therapy. In this proposal, we are hypothesizing that one mechanism by which these tumors escape immune detection is because of a loss of NKT cell function due to the upregulation of inhibitory lipids produced by breast cancers. This work is important because specific lipid inhibitors could serve as potential prophylactic agents to prevent breast cancer in this high-risk group, and could be used as a novel therapeutic for patients who are refractory to other, more conventional treatments. The lipid biosynthesis inhibitors that we are using in these studies have already been approved for clinical use for the treatment of other diseases, so we believe that these studies will lead to clinical trials for the treatment of breast cancer within the next five years.